The Acquired Immunodeficiency Syndrome (AIDS), caused by the human immunodeficiency virus type-1 (HIV-1), is one of the ten leading causes of death in the world (Koutsilieri, 2001). According to a June 2000 World Health Organization (WHO) report on global human immunodeficiency virus (HIV)/AIDS pandemic, nearly 35 million adults and 2 million children worldwide are infected with HIV and it is estimated that one third of the adults and more than one half of the children will develop a dementing illness.
This virus, transmitted by sexual contact or exposure to infected blood products, has to this point eluded attempts at eradication and continues to spread through human populations in both industrialized and non-industrialized nations. Although modern anti-viral medications may control viral replication and prolong life, there is currently no preventative vaccine and no examples of a cure (Glass, 2001).
A variety of neurological syndromes occur throughout the course of HIV infection, affecting the central nervous system, peripheral nervous system, and muscle. The sequelae of HIV infection can be categorized as either related to opportunistic infections of the nervous system, or as direct or indirect effects of the virus itself. Some disorders are manifested early and some late during the infectious process, and the pathological changes include inflammatory, demyelinating, and degenerative changes. This spectrum of diseases associated with a single virus infection is unique in virology.
Neurological disease occurs rarely at the time of initial infection with HIV, even before seroconversion, and prior to the profound immunosuppression of the latter stages of HIV infection. These early manifestations include aseptic meningitis or encephalitis, acute and chronic inflammatory demyelinating polyneuropathies, mononeuritis multiplex associated with peripheral nerve vasculitis, and HIV-associated polymyositis (McArthur, 1987).
Oxidative stress has been implicated in a variety of diseases and pathological conditions, including endothelial cell cytotoxicity, cancer, and coronary heart diseases, such as thrombosis and hyperlipemia (Addis, 1995). Recent studies have shown that elevated lipid peroxidation levels (oxidative stress) may play a role in the pathogenesis of Alzheimer's disease which includes a group of neurodegenerative disorders with diverse etiologies, but the same hallmark brain lesions (Practico, 1998).
Clinical studies have established that elevated plasma concentrations of LDL are associated with atherosclerosis, a most prevalent cardiovascular disease and the principle cause of heart attack, stroke and vascular circulation problems (Sarkkinen, 1993). It is believed that a reduction of atherogenic lipid peroxides, which are transported in the LDL fraction of blood serum, can reduce the risk of atherogenesis (Mazur, 1999). Antioxidants limit oxidative modification of LDL and consequently lower plasma concentrations of LDL, thereby acting as anti-atherogenic compounds (Sarkkinen, 1993). The oxidation of LDL has been reported as a model for testing the ability of polyphenols to act as antioxidants by breaking the peroxidative cascade described above (Rice-Evans, 1995).
A safe, relatively inexpensive, orally administered neuro protectant that reduces the sequelae of cerebral oxidative stress in the setting of HIV-associated brain disease would have great value as an adjunctive therapy. Benefits include those based on evidence regarding the effect of free-radical damage of oxidative stress on key organ systems. They include cerebral antioxidant activity with reduction of ongoing brain injury (Shi 1998; Treitinger 2000); antiviral effects (oxidative stress activates a transcription factor necessary for HIV replication, and phenols are effective in vitro against HIV-1: Ng, 1997); and antiatherosclerotic cardiovascular benefits. Of note, cardiovascular risk has become a concerning issue among HAART-treated individuals as the incidence of severe hyperlipidemia has increased (Lipodystrophy Syndrome). Oxidative stress inhibits the key enzyme responsible for the transfer and metabolism of cell-derived cholesterol via HDL. Antioxidant therapy increases the capacity of HDL for cholesterol uptake, and could lower cholesterol. In addition, antioxidants have been shown in vitro and in vivo to decrease oxidized LDL, strongly implicated as a mediator of endothelial damage of cardiovascular disease (Caruso 1999, Napoli 2001).